Total synthesis of marinomycin a based on a direct dimerization strategy

Article abstract of DOI:10.1002/anie.201404408

The asymmetric total synthesis of (+)-marinomycinA, a 44-membered macrodiolide antitumor agent and antibiotic isolated from a marine actinomycete, Marinispora strain CNQ-140, is reported. The key features of the synthesis include the highly convergent stereocontrolled construction of the monomeric hydroxy salicylate starting from asymmetric epoxidation of the σ-symmetrical dialkenyl carbinol, and an unprecedented direct dimerization through NaHMDS-promoted double transesterification.

Full text of DOI:10.1002/anie.201404408

Angewandte
Chemie
DOI: 10.1002/anie.201404408
Natural Product Synthesis
Total Synthesis of Marinomycin A Based on a Direct Dimerization
Strategy**
Tatsuya Nishimaru, Masashi Kondo, Kimito Takeshita, Keisuke Takahashi, Jun Ishihara, and
Susumi Hatakeyama*
Abstract: The asymmetric total synthesis of (+)-marinomy-
cin A, a 44-membered macrodiolide antitumor agent and
antibiotic isolated from a marine actinomycete, Marinispora
strain CNQ-140, is reported. The key features of the synthesis
include the highly convergent stereocontrolled construction of
the monomeric hydroxy salicylate starting from asymmetric
epoxidation of the s-symmetrical dialkenyl carbinol, and an
unprecedented direct dimerization through NaHMDS-pro-
moted double transesterification.
cus faecium (VREF), and inhibit cancer cell proliferation in
the National Cancer Instituteꢀs 60 cell-line panel (LC50 = 0.2–
2.7 mm) with excellent selectivity against six of the eight
melanoma cell lines.[1] It has been shown that marinomycin A
(1) is the most potent and the presumed true natural product,
which photochemically isomerizes to marinomycins B (2) and
C (3).[1,2] The significant biological properties and structural
challenges have made the marinomycins attractive targets for
synthesis, and the total synthesis of 1 has been accomplished
by Nicolaou et al.,[2] followed by Evans et al.[3] Furthermore,
the synthesis of the monomeric counterpart of 1 was reported
by Cossy et al.[4] Herein we report a novel convergent
asymmetric total synthesis of (+)-marinomycin A (1) that
makes use, for the first time, of a direct dimerization
methodology for the construction of its 44-membered macro-
diolide skeleton.
I
n 2006, Fenical et al. disclosed the isolation of marinomy-
cins A–C (1–3), structurally novel 44-membered C2-symmet-
rical dimeric polyene-polyol macrolides, from the saline
culture broth of a marine actinomycete, Marinispora strain
CNQ-140, which was cultured from a sediment sample
collected deep off the coast of La Jolla in California
(Figure 1).[1]
Given the C2-symmetrical dimeric macrodiolide structure,
one of the most attractive and efficient approaches is the
direct dimerization of a monomeric hydroxy salicylate
through using the benzo[1,3]dioxinone functionality (salicylic
acid acetonide) as an active ester[3,5] in a double transesteri-
fication reaction (Scheme 1). However, it is a formidable
challenge to realize this desired dimerization mode as
opposed to the competitive intramolecular lactonization,
which gives the corresponding 22-membered macrolide, or
intermolecular oligomerization.[6] In this context, we expected
that the judicious selection of appropriate protecting groups
would make the conformation of a monomeric hydroxy ester
ideal for the direct dimerization. In light of the conforma-
tional benefit arising from a dioxane protecting group for the
macrodiolide formation as suggested by Evans et al.,[3] we
temporarily selected compound 4 as the monomeric precursor
since this compound seemed to be conformationally favorable
for dimerization over intramolecular macrolactonization.[7]
We envisioned that compound 4 could be prepared by
Suzuki–Miyaura coupling[8] of the known aromatic fragment
Figure 1. Marinomycins A, B, and C.
These natural products exhibit potent antibiotic activity
(MIC90 = 0.1–0.6 mm) against methicillin-resistant Staphylo-
coccus aureus (MRSA) and vancomycin-resistant Enterococ-
5
[2] and boronate fragment 6. Fragment 6 was considered to be
accessible from alkyne 7 and epoxide 8 through an acetylene–
epoxide coupling,[9] inversion of the C25 stereochemistry, and
Takai olefination.[10] Both alkyne 7 and epoxide 8 would in
turn be derived from the readily available 1,3-diol chiral
building block 9 through a method we have previously
developed.[11]
[*] T. Nishimaru, M. Kondo, K. Takeshita, Dr. K. Takahashi,
Dr. J. Ishihara, Prof. Dr. S. Hatakeyama
Graduate School of Biomedical Sciences, Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852-8521 (Japan)
E-mail: susumi@nagsaki-u.ac.jp
The synthesis of alkyne 7 commenced with the four-step
preparation of enantiopure acetonide 9 from s-symmetrical
dialkenyl carbinol 10 in a sequence involving a Katsuki–
Sharpless asymmetric epoxidation,[12] Mitsunobu inversion,
Red-Al reduction of an epoxy alcohol with concomitant loss
of a benzyloxy group as in 14, and acetonide formation,
[**] This work was supported by the Grant-in-Aid (25253002) from JSPS
and the Grant-in-Aid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocatalysis” (No.
2304) (24105526) from MEXT.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404408.
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Scheme 2. Reagents and conditions: a) Ti(OiPr)4 (10 mol%), d-DIPT
(14 mol%), 4 ꢀ MS, TBHP, CH2Cl2, À258C, 98% (99% ee); b) DEAD,
PPh3, p-nitrobenzoic acid, toluene, À308C then K2CO3, MeOH, 74%;
c) Red-Al, toluene, 08C to reflux, 82%; d) 2,2-dimethoxypropane, PPTS,
acetone, 99%; e) PdCl2 (10 mol%), CuCl, O2, DMF/H2O (10:1), 82%;
f) (EtO)2P(O)CH2CO2Et, NaH, THF, 90% (E/Z=6:1); g) DIBAL-H,
CH2Cl2, À788C, 99%; h) TBDPSCl, imidazole, DMF; i) Li, naphthalene,
THF, À508C, 96% (2 steps); j) (COCl)2, DMSO, Et3N, CH2Cl2, À788C;
k) MeCOC(N2)P(O)(OEt)2, K2CO3, MeOH, 88% (2 steps). DIPT=di-
isopropyl tartrate, TBHP=tert-butyl hydroperoxide, DEAD=diethyl
azodicarboxylate, Red-Al=sodium bis(2-methoxyethoxy)aluminum hy-
dride, PPTS=pyridinium 4-toluenesulfonate, DMF=N,N-dimethyl-
formamide, THF=tetrahydrofuran, DIBAL-H=diisobutylaluminum hy-
dride, DMSO=dimethyl sulfoxide, Red-Al=sodium bis(2-methoxyeth-
oxy)aluminum hydride.
Scheme 1. A retrosynthetic analysis of 1. TBS=tert-butyldimethylsilyl,
BOM=benzyloxymethyl, TBDPS=tert-butyldiphenylsilyl, Bn=benzyl.
according to our established procedure[11] (Scheme 2).
Wacker oxidation[13] of 9 delivered methyl ketone 11, which
was subjected to Horner–Wadsworth–Emmons olefination to
afford a 6:1 mixture of E-ester 12, the Z-isomer of which was
chromatographically separated. Upon successive DIBAL-H
reduction, silylation, and debenzylation[14] with lithium naph-
thalenide, 12 afforded alcohol 13 in excellent yield. After
Swern oxidation of 13, the resulting aldehyde was then
subjected to Seyferth–Gilbert homologation by using the
Ohira–Bestmann reagent[15] to provide alkyne 7. The overall
yield of 7 from 10 was 31% (11 steps).
Scheme 3. Reagents and conditions: a) Li, naphthalene, THF, À508C,
98%; b) MsCl, NEt3, CH2Cl2, 99%; c) LiAlH4, Et2O, reflux, then 1m
HCl, MeOH, 84%; d) nBuLi, THF, À788C, then CO2, I2, 86%;
e) TBSCl, imidazole, DMF, 78%; f) K2CO3, MeOH, 93%; g) BnOCH2Cl,
iPr2NEt, CH2Cl2, 100%. Ms=methanesulfonyl.
Epoxide 8 was also prepared from 9 by a highly diaste-
reoselective seven-step transformation in 51% overall yield
(Scheme 3). Reductive debenzylation of 9 followed by
mesylation of the resulting alcohol gave mesylate 15 in
quantitative yield. Mesylate 15 was then reduced with LiAlH4
and the reaction mixture was directly acidified by the addition
of aqueous HCl and MeOH to afford 1,3-diol 16 without
serious loss of the initially formed volatile product. According
to Cardilloꢀs method,[16] 16 was lithiated and reacted with CO2
followed by I2 to provide iodocarbonate 17 as a single
diastereomer in good yield. Silylation of 17 followed by
methanolysis gave epoxy alcohol 18, which was then pro-
tected as the corresponding BOM ether to provide epoxide 8.
With the required alkyne 7 and epoxide 8 in hand, the
stage was set for the preparation of monomeric hydroxy
salicylate 4 starting from the union of these two fragments
(Scheme 4). The lithium acetylide generated from 7 was
Although several attempts to reduce 19 to E-alkene 21 by
using Red-Al or LiAlH4 met with failure, we found that
Trostꢀs procedure,[17] which involves silylation, intramolecular
hydrosilylation, and desilylation, effected this transformation
satisfactorily. Silylation of 19 with 1,1,3,3-tetramethyldisila-
zane followed by intramolecular hydrosilylation with
[Cp*Ru(MeCN)3]PF6 as the catalyst furnished dihydrooxasi-
line 20, which was then directly subjected to AgF-mediated
desilylation to afford E-alkene 21 and diol 22 in 52% and
34% yields, respectively. Since 22 was quantitatively con-
verted into 21 by selective silylation, the total yield of 21 was
86%. Protection of the secondary alcohol of 21 as the
corresponding TBS ether followed by removal of the BOM
group of 23 by using lithium naphthalenide[14] produced
[9]
reacted with 8 in the presence of BF3·OEt2 to give
homopropargyl alcohol 19 in almost quantitative yield.
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26 in good yield. After TEMPO oxidation of 27, the resulting
aldehyde was directly subjected to Takai olefination with
pinacol (dichloromethyl)boronate[10] to stereoselectively pro-
duce E-boronate 6. Without purification, boronate 6 was then
coupled to the aromatic fragment 5 under Suzuki–Miyaura
reaction conditions to furnish the required monomeric
hydroxy salicylate 4 in 48% overall yield from 27.
To complete the total synthesis, we addressed the crucial
direct dimerization of monomer 4 under various transesteri-
fication conditions. As shown in Table 1, when this reaction
Table 1: Base-promoted dimerization of 4.
Yield [%][a]
of 28
Entry
Method[b]
Base
Recovered 4
1
2
3
4
5
A
A
A
A
B
NaHMDS
KHMDS
LHMDS
LDA
30
9
6
6
71
14
45
32
20
0
NaHMDS
[a] Yield of isolated product. [b] Method A: base (2 equiv) in THF (1.0m)
was added to a THF solution of 4 (0.05m) at À108C and the mixture was
stirred at À108C for 2 min. Method B: compound 4 in THF (0.036m) was
added to NaHMDS (4 equiv) in THF (0.014m) at À108C over 30 min and
the mixture was stirred at À108C for 15 min.
was conducted by adding NaHMDS, KHMDS, LHMDS, or
LDA to a THF solution of 4 at À108C, the production of the
desired 44-membered macrodiolide 28 was observed within
2 min but the yields of isolated product were 30% at best
owing to rather fast decomposition of 4 (entries 1–4).
Lowering the reaction temperature did not improve the
yield of 28 at all. However, to our delight, reverse slow
addition of 4 to NaHMDS in THF at À108C dramatically
improved the dimerization reaction and 28 was isolated in
71% yield (entry 5). In this reaction, the corresponding 22-
membered macrolide and oligomers were not identified.
Finally, exposure of 28 to aqueous HClO4 enabled the
removal of all of the protecting groups to cleanly furnish
marinomycin A (1) in 71% yield without isomerization of the
labile tetraene functionality after reverse phase ODS column
chromatography. The synthetic marinomycin A (1) exhibited
spectral properties identical in all respects to those reported
for the natural product.[1,3]
In conclusion, we have accomplished the convergent total
synthesis of (+)-marinomycin A (1) in 24 steps (the longest
linear sequence) in 4.0% overall yield starting from asym-
metric epoxidation of s-symmetrical dialkenyl carbinol 10.
The synthesis is practical and enables us to obtain hundred mg
quantities of marinomycin A (1). The present work presents
the first successful example of a direct dimerization approach
to marinomycin A (1).
Scheme 4. Reagents and conditions: a) 7, nBuLi, BF3·Et2O, THF,
À788C, then 8, À788C, 97%; b) 1,1,3,3-tetramethyldisilazane, then
[Cp*Ru(MeCN)3]PF6 (10 mol%), CH2Cl2; c) AgF, THF/MeOH/DMSO/
H2O (10:6:3:2), 21 (52%), 22 (34%); d) TBSCl, imidazole, DMF, 97%;
e) Li, naphthalene, THF, À608C, 100%; f) DEAD, PPh3, 4-nitrobenzoic
acid, toluene/THF (1:3), 76%; g) TBAF, AcOH, DMF, 89%;
h) NaOMe, THF/MeOH (1:2), 100%; i) TEMPO, PhI(OAc)2, phosphate
buffer (pH 7.0), MeCN, 08C, 97%; j) Cl2CHB(pin), CrCl2, LiI, THF;
k) 5, Pd(PPh3)4 (40 mol%), 0.5m aq KOH, THF, 258C, 10 min, 48% (2
steps); l) NaHMDS, THF, À108C, 71%; m) 3.0m HClO4/THF (1:5),
71%. TBAF=tetra-n-butylammonium fluoride, TEMPO=2,2,6,6-tetra-
methyl-l-piperidinoxyl (free radical), HMDS=1,1,1,3,3,3-hexamethyldi-
silazane.
Received: April 17, 2014
Published online: && &&, &&&&
alcohol 24 in almost quantitative yield. Mitsunobu inver-
sion[18] of the C25 hydroxy group afforded 4-nitrobenzoate 25,
which, upon selective desilylation[19] and methanolytic
removal of the 4-nitrobenzoyl group, delivered diol 27 via
Keywords: antibiotics · antitumor agents · macrodiolides ·
natural products · total synthesis
.
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owing to the proximity of the reaction sites (3.489 ꢁ). See the
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[7] Molecular mechanical calculations (MMFF*, Macro Model 8.6)
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4
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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Angewandte
Chemie
Communications
Natural Product Synthesis
Seeing double: The asymmetric total
synthesis of (+)-marinomycin A, a 44-
membered macrodiolide antitumor agent
and antibiotic, is reported. The key fea-
tures of the synthesis include the highly
convergent stereocontrolled construction
of the monomeric hydroxy salicylate
starting from asymmetric epoxidation of
the s-symmetrical dialkenyl carbinol, and
an unprecedented direct dimerization
through NaHMDS-promoted double
transesterification.
T. Nishimaru, M. Kondo, K. Takeshita,
K. Takahashi, J. Ishihara,
S. Hatakeyama*
&&&& — &&&&
Total Synthesis of Marinomycin A Based
on a Direct Dimerization Strategy
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!